Cardioprotective Actions of a Glucagon-like Peptide-1 Receptor Agonist on Hearts Donated After Circulatory Death

• Published in: Journal of the American Heart Association Vol. 12; no. 3; p. e027163
• Main Authors: Kadowaki, Sachiko, Siraj, M Ahsan, Chen, Weiden, Wang, Jian, Parker, Marlee, Nagy, Anita, Steve Fan, Chun-Po, Runeckles, Kyle, Li, Jing, Kobayashi, Junko, Haller, Christoph, Husain, Mansoor, Honjo, Osami
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 07-02-2023; Wiley
• Subjects: Animals; donation after circulatory death heart; Exenatide - pharmacology; Glucagon-Like Peptide-1 Receptor - agonists; glucagon‐like peptide‐1; Heart; Heart Transplantation - adverse effects; Heart Transplantation - methods; ischemia reperfusion injury; Nitric Oxide Synthase Type III; Original Research; pediatric heart transplantation; pig; Reperfusion Injury; Swine; donation after circulatory death heart; ischemia reperfusion injury; pediatric heart transplantation; glucagon‐like peptide‐1; pig
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.122.027163

Background Heart transplantation with a donation after circulatory death (DCD) heart is complicated by substantial organ ischemia and ischemia-reperfusion injury. Exenatide, a glucagon-like peptide-1 receptor agonist, manifests protection against cardiac ischemia-reperfusion injury in other settings. Here we evaluate the effects of exenatide on DCD hearts in juvenile pigs. Methods and Results DCD hearts with 15-minutes of global warm ischemia after circulatory arrest were reperfused ex vivo and switched to working mode. Treatment with concentration 5-nmol exenatide was given during reperfusion. DCD hearts treated with exenatide showed higher myocardial oxygen consumption (exenatide [n=7] versus controls [n=7], over 60-120 minutes of reperfusion,
<0.001) and lower cardiac troponin-I release (27.94±11.17 versus 42.25±11.80 mmol/L,
=0.04) during reperfusion compared with controls. In working mode, exenatide-treated hearts showed better diastolic function (dp/dt min: -3644±620 versus -2193±610 mm Hg/s,
<0.001; Tau: 15.62±1.78 versus 24.59±7.35 milliseconds,
=0.02; lateral
' velocity: 11.27 ± 1.46 versus 7.19±2.96,
=0.01), as well as lower venous lactate levels (3.17±0.75 versus 5.17±1.44 mmol/L,
=0.01) compared with controls. Higher levels of activated endothelial nitric oxide synthase (phosphorylated to total endothelial nitric oxide synthase levels: 2.71±1.16 versus 1.37±0.35,
=0.02) with less histological evidence of endothelial damage (von Willebrand factor expression: 0.024±0.007 versus 0.331±0.302, pixel/μm,
=0.04) was also observed with exenatide treatment versus controls. Conclusions Acute treatment of DCD hearts with exenatide limits myocardial and endothelial injury and improves donor cardiac function.